Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Abstract

Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

Keywords: Cadherin; Integrin; Myofibroblast.

Fig. 1.

Relevance of adhesion mechanobiology to fibrotic heart disease. (A) Fibrotic disease affects both heart valves and heart myocardium and is characterized by changes in the mechanical properties of the ECM (extracellular matrix) and the cellular phenotypes present in the tissue. Healthy valves primarily have quiescent fibroblast-like cells called valvular interstial cells (VICs) that are embedded in a stable, organized ECM and surrounded by a single layer of valvular endothelial cells (VECs). Similarly, healthy myocardium contains cardiomyocytes (CMs), cardiac fibroblasts (CFs) and lined blood vessels lined with endothelial cells (ECs) that are embedded in stable ECM. Disease can be initiated by acute or chronic cardiac conditions. Inflammation initiates ECM breakdown, accumulation of inflammatory cells and fibroblast-like cells, as well as EndMT, which yields endothelial-to-mesenchymal-transformed cells (EndMTCs). Inflammation can turn into fibrosis, which is characterized by accumulation of stiff ECM and a large number of myofibroblasts (MyoFBs) that are derived from VICs, CFs, and EndMTCs. MyoFBs are particularly relevant to disease because they are able to initiate ECM remodeling and intercellular signaling pathways. (B) The MyoFB phenotype is promoted by combined inputs of mechanical and chemical signals that are transduced, respectively, through integrins and cadherins, and signaling factor receptors. Increased expression of α-SMA in MyoFBs stabilizes, and further activates integrins and cadherins; this increases the generation of intracellular force and actively remodels the ECM. MyoFBs also express ECM and growth factors that not only affect themselves but also neighboring cells.

Fig. 2.

Mechano-sensitive mechanisms of MyoFB differentiation. (A–C) Myofibroblasts (MyoFBs) play a central role in in the progression of fibrotic disease in the heart because of their roles in the generation and transmission of cellular force, intercellular signaling and ECM remodeling. One important mechanism yielding MyoFBs is EndMT (A), by which endothelial cells (ECs) lose their endothelial markers (including VE-cadherin) and become migratory and contractile. Valvular interstitial cells (VICs) and cardiac fibroblasts (CFs) can differentiate into MyoFBs in response to high mechanical strain (B) – which is often experienced during inflammation – with the degradation of initial ECM and a corresponding decrease in tissue stiffness. Quiescent VICs and CFs can also differentiate into MyoFBs in response to high mechanical stress (C), caused by both increased tissue stiffness and increased tissue forces. MyoFBs increase the overall stress in the environment by producing excess ECM and contracting existing ECM through increased cellular contractility. MyoFBs also release profibrotic signaling factors, including TGF-β1 and Wnt, that promote further MyoFB differentiation and tissue stiffening. This forms a positive feedback loop leading to progressively worsening fibrosis. Tissue stiffening also often leads to compensatory increases in ventricular pressure, which increases the applied tissue forces and reinforces this positive feedback loop.

Fig. 3.

Crosstalk between growth factor and adhesion protein signaling. Illustrated here are the intracellular signaling pathways and crosstalk between integrin, growth factor and cadherin signaling. β3 integrin signals through the same intracelullar pathways as TGF-β1, which increase expression of α-SMA and cellular contractility. β1 integrin shares pathways with both TGF-β1 and FGF, which may in part explain its context-dependent effects on MyoFB differentiation. Cadherins regulate the availability of β-catenin to participate in Wnt signaling, a pathway that promotes cadherin switching and fibrosis. Both integrins and cadherins mechanically link the ECM and the actin cytoskeleton, and are sensitive to increases in applied force from extracellular or intracellular sources; therefore, increased expression of α-SMA in MyoFBs forms a positive feedback loop to further promote adhesion stability and associated signaling pathways.